The overall goal of this Schizophrenia Research Center at Johns Hopkins is to conduct interdisciplinary studies towards understanding the molecular pathology of schizophrenia. One of the recent exciting developments in schizophrenia research is the identification of disease susceptibility genes from human genetic association studies. Functional studies of each susceptibility factor have suggested that, instead of functioning independently from each other, these factors act synergistically in several common "pathways" that may contribute to the disease pathology. Accumulating evidence also reinforces the emerging view that schizophrenia is a condition of neuronal development with an adult onset. How specific schizophrenia susceptibility factors, or pathways, regulate different aspects of neuronal development, however, is largely unknown. Our collaborative team has obtained compelling evidence from our preliminary studies that DISC1 interacts with other susceptibility factors as an adaptor and is involved in various phases of neurodevelopment. Thus, we hypothesize that DISC1 is a promising lead with which we can explore the disease "pathways" underlying the pathology of schizophrenia associated with neurodevelopment. On the basis of preliminary data that our group and others have collected, we hypothesize three aspects of neurodevelopment as an important foundation for studying and elucidating the pathology. These include: (1) synaptic formation in the developing cerebral cortex;(2) centrosomal organization in the developing cerebral cortex;and (3) neurogenesis in the hippocampus, which will be studied in each project (Projects 1-3), respectively. Core A will provide administration and overall scientific direction. Core B will characterize behavioral phenotypes/endophenotypes of mice under study as models for the molecular cellular biology in the three projects. Core C will conduct genetic studies exploring possible genetic variations in the targets originally from biological studies, which, in turn, will be studied in each project. The ultimate goal is to elucidate the disease "pathways" to have better understanding of the disease, build appropriate models for mechanistic studies and future therapeutic strategies, and eventually to identify novel ways to treat the disease.